The avermectin compounds are a series of compounds which are isolated from the fermentation broth of Streptomyces avermitilis. The morphological characteristics of the culture, as well as the fermentation methods and processes of isolation of the avermectin compounds is described in U.S. Pat. No. 4,310,519.
The avermectin compounds have the following structure: ##STR1## wherein
R is hydrogen, hydroxy, the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group of the structure: ##STR2## and wherein the broken line at the 22,23-position indicates a single or double bond provided that the double bond is present only when R.sub.2 is iso-propyl or sec butyl;
R.sub.1 is hydrogen or hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is methyl, ethyl iso-propyl or sec-butyl; and
R.sub.3 is methoxy or hydroxy.
The compounds wherein R.sub.3 is hydroxy are the compounds prepared by the process of this invention.
There are eight different avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b, based upon the structure of the individual compounds.
With reference to the R.sub.1, R.sub.2 and R.sub.3 groups of the above structural formula, the individual avermectin compounds, as described in U.S. Pat. No. 4,310,519, are as set forth below (the R group is 4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a Double Bond sec-butyl --OCH.sub.3 A1b Double Bond iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2b --OH iso-propyl --OCH.sub.3 B1a Double Bond sec-butyl --OH B1b Double Bond iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
The compounds wherein R.sub.2 is methyl or ethyl are disclosed in U.S. Pat. No. 3,950,360 to Aoki et al. and are identified as B-41 or milbemycin compounds. Such compounds have the same 16-membered macrocyclic ring as the avermectin compounds, however, the substitution pattern, particularly at the 13-, 22-, 23- and 25-positions are differrent. Those B-41 or milbemycin compounds with a 5-methoxy group have been found to be convertible to the 5-hydroxy compound using the process of this invention.
In addition, derivatives of the avermectin compounds have been prepared. In particular, the 22,23-dihydro derivatives of the 1-series of compounds have been found to have particularly advantageous biological properties. The 22,23-dihydro B1a/B1b derivatives are prepared by selectively hydrogenating the 22,23 unsaturated precursor. That is, such compounds are prepared from the avermectin B1a/B1b pair of compounds. The 22,23 dihydro compounds and their preparation are described in European published patent application Ser. No. 8300435.1. This, of course, requires that the avermectin B1a/B1b pair of compounds be separated from the A1a/A1b, A2a/A2b and B2a/B2b pairs of compounds, and then reduced to prepare the dihydro derivatives. The main problem encountered with this procedure is that the A1a/A1b, A2a/A2b and B2a/B2b compounds remain unused, and in effect wasted. In particular, it is desirable to convert the A compounds into the B compounds, since the B-compounds, with the 5-hydroxy group, have a higher level of antiparasitic activity than the A compounds.
The process of the instant invention reduces this waste by converting the unused A compounds into B compounds. The B compounds, particularly the B1a/B1b compounds, are preferred for their biological activity. Thus by converting unused A1a/A1b compounds into B1a/B1b compounds, additional precursors to the most preferred compounds are made available. Since such precursors are available only by fermentation techniques, no synthetic schemes being available, the increased yield of the preferred precursor represents a considerable savings.